Molecular Mechanisms Underlying the Muscle Response to Exercise-Induced Muscle Damage in Chronic Cigarette Smokers

Smoking increases risk for musculoskeletal injury and protracts healing. The underlying mechanisms have not been explored, yet dysregulated inflammatory responses may contribute. To investigate these risks, Study 1 of this dissertation monitored typical responses to muscle damaging eccentric contractions (ECC) in smokers and nonsmokers. Smokers experienced greater muscle fatigue both during and immediately after ECC and greater delayed hyperalgesia, a phenomenon known as delayed onset muscle soreness (DOMS), than did non-smokers. DOMS (driven by inflammation) peaks 48h after ECC, when there is a shift from pro- to anti-inflammatory signaling; thus I chose to investigate this time further in smokers. The “late inflammation” time point is relatively unstudied mechanistically. Therefore, in Study 2 I further characterized the post-ECC muscle response in non-smokers and focused on hyperalgesic pathways. Transcriptome analyses revealed greater proliferation and pro-inflammatory signaling at 3h, which returned to baseline by 48h. Activity of key regulatory pathways canonical (p65) nuclear factor kappa-beta (NFκB) and extracellular regulated kinase (ERK)1/2 mimicked the pro- (activated) to anti- viii inflammatory (de-activated) shift. In addition, nerve growth factor (NGF), a hyperalgesic-modifier, was also induced. Further testing revealed suppressed 48h p65 activity. In Study 3 I tested these pathways, and non-canonical NFκB (REL-B) signaling (specifies oxidative muscle fibers), in skeletal muscle from smokers and non-smokers 48h post-ECC. Smokers had fewer oxidative (Type I) muscle fibers. Further, REL-B, enhanced in non-smokers at 48h, was suppressed in smokers. These findings may explain the greater fatigue in smokers, which can increase risk for injury. p65 activity, suppressed at 48h in non-smokers, was unchanged in smokers, suggesting delayed pro-inflammatory resolution. Active and total ERK levels were suppressed, overall, in smokers. While there were no differences in NGF levels or colocalization with the TrkA receptor between smokers and non-smokers, smokers did express higher p75NTR receptor levels, which may activate NFκB and promote hyperalgesia. NGF/p75NTR co-localization at 48h post-ECC decreased in nonsmokers but increased in smokers. Higher DOMS, NGF, and NFκB signaling may indicate prolonged pro-inflammatory signaling, delayed resolution, and protracted healing in smokers. This dissertation provides insights into mechanisms that appear to place smokers at greater risk for musculoskeletal injury and impaired healing

Anaesthesia practices for Caesarean section amongst non-physician anaesthesia providers at an Ethiopian referral hospital

Funding The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This project received funding in the form of a travel bursary from the Association of Anaesthetists, the Obstetric Anaesthetists Association and the Royal College of Medicine, to enable the primary author to conduct this project. Acknowledgments The authors wish to thank the WFSA for providing permission to utilise the behavioural survey.Peer reviewedPostprin

Youth and the communication of Risk: developing connections between cancer council Australia and contemporary online youth culture

Through two focus groups, the project investigated how youth culture perceives online communication of risk. In two 90-minute sessions, investigators gaged the range of online activities that nine 18 - 24 year old university students engaged with. Through a guided discussion the participants explored how they would relate to the communication of health risk more generally and cancer risk more specifically.Participants’ online activity is very high and a range of social media forms are part of their everyday lives. In contrast, their use of traditional media is almost non-existent. Their relationship to accessing and being aware of health information demonstrated a range of views that pointed to quite new and different relationships to health and health professionals. To intersect with their online movements in the communication of health risk demands a sophisticated knowledge of their own searching patterns.Key ideas generated from the focus groups include: that it might be advantageous to group health risk beyond the specificity of cancer for online success; that an online persona would be useful to provide a face for the communication of risk; that a multi-platform campaign to raise the profile of a persona would be useful; and that success means moving between the serious and the light-hearted in a way that makes the persona a complete person of interest for them

How should long-term free-living physical activity be targeted after stroke? A systematic review and narrative synthesis

Abstract Background Increasing physical activity (PA) levels (regular movement such as walking and activities of daily living) and reducing time spent sedentary improves cardiovascular health and reduces morbidity and mortality. Fewer than 30% of independently mobile stroke survivors undertake recommended levels of PA. Sedentary behaviour is also high in this population. We aimed to systematically review the study characteristics and the promise of interventions targeting free-living PA and/or sedentary behaviour in adult stroke survivors. Methods Seven electronic databases were searched to identify randomised controlled trials (≥3-months follow-up) targeting PA and/or sedentary behaviour in adults with first or recurrent stroke or transient ischaemic attack. The quality assessment framework for RCTs was used to assess risk of bias within and across studies. Interventions were rated as “very”, “quite” or “non-promising” based on within- or between-group outcome differences. Intervention descriptions were captured using the TIDieR (Template for Intervention Description and Replication) Checklist. Behaviour change techniques (BCTs) within interventions were coded using the BCT Taxonomy v1, and compared between studies by calculating a promise ratio. Results Nine studies fulfilled the review criteria (N = 717 randomised stroke patients) with a high or unclear risk of bias. None of the studies targeted sedentary behaviour. Six studies were very/quite promising (reported increases in PA post-intervention). Studies were heterogeneous in their reporting of participant age, time since stroke, stroke type, and stroke location. Sub-optimal intervention descriptions, treatment fidelity and a lack of standardisation of outcome measures were identified. Face to face and telephone-based self-management programmes were identified as having promise to engage stroke survivors in PA behaviour change. Optimal intensity of contact, interventionist type and time after stroke to deliver interventions was unclear. Nine promising BCTs (ratios ≥2) were identified: information about health consequences; information about social and environmental consequences; goal setting-behaviour; problem-solving; action planning; feedback on behaviour; biofeedback; social support unspecified; and credible source. Conclusions Future research would benefit from establishing stroke survivor preferences for mode of delivery, setting and intensity, including measurement of physical activity. Interventions need to justify and utilise a theory/model of behaviour change and explore the optimal combination of promising BCTs within interventions

Pretend Play and Social Engagement in Toddlers at High and Low Genetic Risk for Autism Spectrum Disorder

Toddlers with an older sibling with autism spectrum disorder (ASD) and low risk (LR) toddlers with typically-developing older siblings were observed during free play with a parent and elicited pretend with an examiner at 22-months. Functional and pretend play, children’s social engagement, and parent sensitivity were assessed during free play. Complexity of play was assessed during the elicited pretend task. Toddlers with an ASD diagnosis showed less pretend play across contexts and less social engagement with parents or the examiner than either LR toddlers or high risk toddlers without a diagnosis (HR-noASD). Lower levels of pretend play and social engagement were associated with symptom severity within the high risk group, reflecting emerging ASD in toddlerhood

From the Anthropocene to mutual thriving: An Agenda for higher education in the Ecozoic

Higher education in the global North, and exported elsewhere, is complicit in driving the planet\u27s socio-ecological crises by teaching how to most effectively marginalize and plunder Earth and human communities. As students and activists within the academic system, we take a firm stand to arrest this cycle, and to redirect education toward teaching how to create conditions for all life to thrive. In this paper, we articulate a research and education agenda for co-constructing knowledge and wisdom, and propose shifts in the \u27ologies from the current, destructive modes to intended regenerative counterparts. We offer to shift from an ontology of separation to that of interconnectedness; from an epistemology of domination to that of egalitarian relationship; and from an axiology of development to that of plural values for world- and meaning-making. Such paradigm shifts reflect the foundational aspirations of the consilient transdiscipline of ecological economics. We analyze several introductory university textbooks in economics, law, and natural sciences, to demonstrate how destructive \u27ologies are taught in North American universities, and how such teaching implicitly undermines critical inquiry and effective challenge. Our strategy for change is to provide a new theoretical framework for education: the regenerative \u27ologies of the Ecozoic\u27, based on biophysicality, embedded relationality, pluralism, and the sustainable well-being of all members in the community of life

Accurate state estimation from uncertain data and models: an application of data assimilation to mathematical models of human brain tumors

<p>Abstract</p> <p>Background</p> <p>Data assimilation refers to methods for updating the state vector (initial condition) of a complex spatiotemporal model (such as a numerical weather model) by combining new observations with one or more prior forecasts. We consider the potential feasibility of this approach for making short-term (60-day) forecasts of the growth and spread of a malignant brain cancer (glioblastoma multiforme) in individual patient cases, where the observations are synthetic magnetic resonance images of a hypothetical tumor.</p> <p>Results</p> <p>We apply a modern state estimation algorithm (the Local Ensemble Transform Kalman Filter), previously developed for numerical weather prediction, to two different mathematical models of glioblastoma, taking into account likely errors in model parameters and measurement uncertainties in magnetic resonance imaging. The filter can accurately shadow the growth of a representative synthetic tumor for 360 days (six 60-day forecast/update cycles) in the presence of a moderate degree of systematic model error and measurement noise.</p> <p>Conclusions</p> <p>The mathematical methodology described here may prove useful for other modeling efforts in biology and oncology. An accurate forecast system for glioblastoma may prove useful in clinical settings for treatment planning and patient counseling.</p> <p>Reviewers</p> <p>This article was reviewed by Anthony Almudevar, Tomas Radivoyevitch, and Kristin Swanson (nominated by Georg Luebeck).</p

Analysis of Epithelial Growth Factor-Receptor (EGFR) Phosphorylation in Uterine Smooth Muscle Tumors

Uterine fibroids are the commonest uterine benign tumors. A potential mechanism of malignant transformation from leiomyomas to leiomyosarcomas has beendescribed. Tyrosine phosphorylation is a key mechanism that controls biological functions, such as proliferation and cell differentiation. The aim of the current study was to evaluate the phosphorylation of epithelial growth factor-receptor (EGFR) in normal myometrium, uterine myomas and uterine leiomyosarcomas. Formalin-fixed paraffin-embedded tissue samples from normal myometrium, leiomyomas and leiomyosarcomas were studied. Samples were immunohistochemically (IHC) assessed using the anti-EGFR phosphorylation of Y845 (pEGFR-Y845) and anti-pEGFR-Y1173 phosphorylation-specific antibodies. IHC staining was evaluated using a semiquantitative score. The expression of pEGFR-Y845 was significantly upregulated in leiomyosarcomas (p < 0.001) compared to leiomyomas and normal myometrium. In contrast, pEGFR-Y1173 did not differ significantly between the three groups of the study. Correlation analysis revealed an overall positive correlation between pEGFR Y845 and mucin 1 (MUC1). Further subgroup analysis within the tumoral group (myomas and leiomyosarcomas) revealed an additional negative correlation between pEGFR Y845 and galectin-3 (gal-3) staining. On the contrary no significant correlation was noted within the non-tumoral group. An upregulated EGFR phosphorylation of Y845 in leiomyosarcomas compared to leiomyomas implicates EGFR activation at this special receptor site. Due to these pEGFR-Y845 variations, it can be postulated that MUC1 interacts with it, whereas gal-3 seems to be cleaved from Y845 phosphorylated EGFR. Further research on this field could focus on differences in EGFR pathways as a potentially advantageous diagnostic tool for investigation of benign and malignant signal transduction processes

Electronic adherence monitoring identifies severe preschool wheezers who are steroid responsive.

Little is known about adherence to inhaled corticosteroids (ICS) in preschool children with troublesome wheeze. Children with aeroallergen senitization, or those reporting multiple trigger wheeze (MTW), are more likely to respond to ICS. We hypothesized that adherence to ICS and symptom control are only positively related in atopic children, or those reporting MTW. Patients aged 1 to 5 years with recurrent wheeze prescribed ICS were recruited from a tertiary respiratory clinic. Clinical phenotype and aeroallergen senitization were determined, and adherence assessed using an electronic monitoring device (Smartinhaler). Symptom control (test for respiratory and asthma control in kids [TRACK]), quality of life (PACQLQ), airway inflammation (offline exhaled nitric oxide) were assessed at baseline and follow-up. Forty-eight children (mean age 3.7 years; SD, 1.2) were monitored for a median of 112 (interquartile range [IQR], 91-126) days. At baseline n = 29 reported episodic viral wheeze and n = 19 reported MTW. Twenty-four out of 48 (50%) wheezers had suboptimal ICS adherence (<80%). Median adherence was 64% (IQR, 38-84). There was a significant increase in TRACK and PACQLQ in the group as a whole, unrelated to adherence. In subgroup analysis only atopic wheezers with moderate or good adherence ≥ 60% had a significant increase in TRACK. There was no relationship between clinical phenotype, and adherence or TRACK. In this pilot study, overall adherence to ICS was suboptimal and was positively related to symptom control in atopic wheezers only. Assessments of adherence are important in preschool troublesome wheezers before therapy escalation to help identify those with an ICS responsive phenotype